Youth obesity is a strong predictor of adult obesity, which has well-known negative health consequences. Thus, addressing adult obesity requires tackling youth obesity. MED4Youth’s main objective is to strengthen the link between the Mediterranean Diet (MD) and the health benefits against youth obesity and associated cardiovascular disease (CVD) risk factors, identifying positive effects exerted by an MD including sourdough bread and healthy products from the Mediterranean basis (chickpeas/hummus, nuts, and pomegranate juice). For this purpose, a multicenter randomized controlled trial in which an MD-based intervention will be compared to a traditional low-fat diet intervention will be carried out with 240 overweight and obese adolescents (13–17 years) from Spain, Portugal, and Italy. Both interventions will be combined with an educational web-application addressed to engage the adolescents through a learning-through-playing approach, using both educational materials and games. To assess the interventions, adherence to the MD, dietary records, physical activity, food frequency, sociodemographic, and quality of life questionnaires as well as classical anthropometric and biochemical parameters will be evaluated. Furthermore, an omics approach will be performed to elucidate whether the interventions can shape the gut microbiota and gut-derived metabolites to gain knowledge on the mechanisms through which the MD can exert its beneficial effects.